DESCRIPTION: The long-term goal is to understand the mechanisms by which lipids regulate gene expression in vascular cells and thereby influence the development cardiovascular disease. The interaction of oxidized low-density lipoprotein with cells of the artery wall is central to the pathogenesis of atherosclerosis. Oxidized lipids not only serve as the substrate for macrophage lipid accumulation, but are also thought to contribute to lesion development through regulation of adhesion molecules and cytokines. This proposal is focused on defining the role of the nuclear receptor PPARgamma in regulating macrophage gene expression and function in response to oxidized lipids. PPARgamma is expressed at high levels in macrophage-derived foam cells of atherosclerotic lesions and is transcriptionally activated by oxidized fatty acid components of oxLDL. Multiple functions have been proposed for this receptor in macrophages, including promotion of cell differentiation, modulation of cytokine expression, and regulation of lipid uptake and metabolism. However, the true role of this transcription factor in macrophage physiology and vascular disease remains unclear. The first aim is to identify target genes of PPARgamma in monocytic cells. The identity of these genes should provide valuable insight into the nature of the processes controlled by this receptor. Preliminary data has identified the nuclear oxysterol receptor LXRa and lipoprotein lipase as regulatory targets for PPARgamma. The second aim is to characterize gene expression and function in genetically defined macrophages that over express or lack PPARgamma. The importance of PPARgamma in regulating lipid metabolism, cytokine production and mediating the biological effects of oxidized lipids on macrophage gene expression will be tested. The third aim is to analyze the role of PPARgamma in macrophage function and atherogenesis in vivo through creation of a macrophage-specific deletion of the PPARgamma gene. These aims are expected not only to advance our understanding of the biologic function of PPARgamma but also to clarify mechanisms by which lipid mediators regulate gene expression during pathologic processes such as inflammation and atherosclerosis.